The rationale for delivering drugs via inhalation varies from class to class. For example, due to the nature of certain respiratory disease states such as infection, inflammation, or bronchoconstriction, it has been found that inhalation is the optimal route of administration to achieve sufficiently high levels of drug in the diseased tissue(s). In some cases, certain agents delivered via inhalation can produce fewer systemic side effects when inhaled, without comprising efficacy, as is the case for some classes of respiratory therapeutics. On the other hand, drugs intended for systemic activity may be delivered via inhalation to take advantage of the high surface area of the lungs, providing rapid drug absorption into the systemic circulation without first pass metabolic effects associated with oral administration. In some situations, delivery of an agent to the lung may be for the convenience of either the patient or healthcare provider. There is currently interest in the development of vaccine delivery to the lungs, which if successful would remove the need for injections as part of routine vaccination. Common medicaments delivered to the lung are drugs for the treatment of asthma and chronic obstructive pulmonary disease (COPD) where the drugs act locally in the lung tissue to prevent or relieve symptoms such as bronchial spasm. Another example would be the delivery of antibiotics to treat the presence of bacterial infections of the lung.
At present there are generally three different methods used for delivery of drugs to the lung. The first involves drug substance dissolved or dispersed in a liquid/gas propellant such as a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFA134a). In these systems, the drug substance and propellant are supplied in a canister which contains a metering valve, the canister being used in conjunction with a device referred to as a pressurized metered dose inhaler (pMDI). At the time of administration, patients are required to coordinate their breath inhalation with actuation of the device. When the device is actuated, the drug substance is aerosolized by the propellant. Pressurized metered dose inhalers have certain disadvantanges which include (in some cases) the use of ozone-depleting propellants (CFCs). Also, upon actuation the drug substance particles exit the devices at high velocities due to the pressures generated by the propellants. This causes much of the dose to impact the patient's throat and be swallowed instead of being delivered to the airways of the lung. Many patients also have difficulty coordinating their breathing with actuation of the devices. For all of the above mentioned reasons, pressurized metered dose inhalers are less than optimal for delivery of drug substance to the lung.
A second method of pulmonary drug delivery involves dissolution or dispersion of the drug substance in water followed by nebulization of the solution or suspension with a compressed air (jet) or ultrasonic nebulizer. This approach is often preferred for pediatric patients who are unable to coordinate their breathing with actuation of a pressurized metered dose inhaler. Drug delivery by nebulization suffers from the disadvantage of being very slow. Typical commercially available nebulizers have delivery rates in the range of ca. 0.25 to 0.50 mL/min, leading to drug administration times of 6 to 7 minutes or longer. Nebulization therapy is inconvenient and requires a high level of patient compliance. For instance, all nebulizers have to be washed and disinfected after each use. Jet nebulizers require the use of an electrically operated air compressor, and ultrasonic nebulizers must be connected to line voltage or require batteries for operation. Some nebulizers which contain mesh screens are only suitable for delivery of drug solutions and cannot be used with suspensions. For all of these reasons, nebulizer use is generally limited to patients who cannot coordinate their breathing with device actuation and to hospitalized patients with breathing tubes in place.
The third method of pulmonary drug delivery is by the inhalation of a dry powder formulation. Drug substance is delivered to the lungs by the patient breathing in the powder from a delivery device positioned in the mouth. Typical dry powder formulations consist of carrier particles of an inert ingredient such as lactose blended with micronized pharmaceutically active agent, although some devices are designed to deliver pure micronized drug substance. The most important property for successful delivery of dry powder inhaled therapeutics is the aerodynamic size of the aerosolized drug particles. Aerodynamic size is a measure of how drug particles behave in an air stream and depends on a variety of factors including the geometric particle size, shape, and density. Aerodynamic size also depends on how readily the particles in a powder can be separated or deaggregated from each other when aerosolized. Thus, small particles which are strongly aggregated may behave like much larger particles when aerosolized. The aerodynamic size determines how far into the lung the particles may penetrate. In general the smaller the particle size, the deeper the particles penetrate into the lung. Inhaled particles smaller than about 1 μm in diameter often do not deposit in the lung but are exhaled back out of the lung. For drugs intended for systemic absorption, deep penetration into the alveolar region of the lung is necessary and particles having an MMAD of 0.5 to 5 (or 1 to 3) μm are generally desirable. For treating COPD, asthma and other diseases of the respiratory tract, topical delivery to upper airways is the aim. Particles with a size of 3 to 5 μm are generally preferred for this purpose because they tend to deposit in the conducting airways of the lung. Most raw drug substance is considerably larger than 1 to 5 μm in diameter, therefore the current methods of making formulations for inhalation requires air jet micronization of the drug substance. Micronization is an effective method of reducing drug particle size, but it tends to impart high levels of electrostatic charge on the particles which causes them to adhere to each other, to carrier particles in the formulation, and to surfaces of dry powder inhaler devices. As a result, the delivery efficiency of conventional dry powder formulations can be relatively low, and in some cases as little as one third of the aerosolized material may be able to reach the patient's respiratory tract.
There are several other critical parameters for successfully delivering therapeutic or pharmaceutical agents by dry powder inhalation. One important parameter is the aerodynamic diameter of the particles, which is a measure of how the particles behave when dispersed in an air stream. In cases where the formulation contains excipients in addition to active agent particles, adequate content uniformity of the powder is another important attribute for accurate delivery of dose. Another critical parameter for inhaled dry powder formulations is the flowability of the powder. The powder in the device used by the patient needs to flow well, so that a full and consistent dose of the powder formulation leaves the device. A further critical parameter for inhaled dry powder formulations is the efficiency of dose delivery, a measure of which is the fine particle fraction (FPF). Thus, the FPF provides an in vitro measure of the efficiency of the device/formulation in delivering the active to the lung.
Despite advances in methods of preparing dry powder formulations, there remains a need for particles with the appropriate properties, such as size, uniformity, flowability, and FPF, for enhanced delivery of therapeutics to the lung. Furthermore, methods are needed which can be readily utilized without limitations imposed by the solubility of the therapeutic agent and are cost-effective to manufacture. These needs and other needs are satisfied by the present invention.